Hormone use and abuse in sports Flashcards
WADA
world anti doping agency
prohibited substances
- anabolic agents
- peptide hormones, growth factor and related substances and memetic
- beta-2 agonists
- hormone and metabolic modulators
- diuretics
- masking agents
why are dieuretics used
short term weight loss
which sports is beta 2 agonist popular in
cycling
prohibited methods
- manipulation of blood & components
- chemical and physical
- gene doping
substances and methods prohibited in competition
- stimulants
- narcotics
- cannabinoids
- glucocorticoids
substances prohibited in particular sports
- alcohol in snooker
- beta blockers in shooting
- narcotics
- cannabinoids
- glucocorticoids
TUEs
therapeutic exemption certificates
e.g lots of cyclists seem to have been prescribed beta agonists and formally declared to have asthma, for bonafide reasons
what supplement is curet under questioning for it s administration and dosage
L-carnitine
L-carnitine
- involved in mitochondrial FA translocation
- during high intensity exercise, formation of acetylcarnitine is essential for maintenance of a viable pool of free co-enzyme A
- this enables PDC & TCA flux to continue
what is the legal asthma drug, found to have been taken at 2 times the allowed level by chris froome
Beta 2 agonist
doping for strength and power training target
muscle mass
doping for endurance training target
aerobic metabolism
three key drugs for doping
- testosterone
- growth hormone
- erythropoietin
what is focus of body building
aesthetics not function and strength
what axis is critical in muscle growth and developemet
GH - IGF1 axis
GH stimulates release of IGFI from the liver.
Muscle takes up IGF1, releases IGF1 and self produces IGF1
effect of IGF1 on muscle
- causes proliferation and differentiation of satellite cells
- stimulates MPS
- inhibits MPB
what does direct infusion of IGF1 do to mice muscles
- causes growth
- has insulin like properties
rhGH
recombinant human growth hormone
effects of rhGH
is it anabolic?
- increases circulating IGF1
- doesn’t increase MPS over and above resistance training
studies show its not anabolic ^
however shown to strengthen connective tissue structure and tendons hence prohibited
why is rhGH prohibited
shown to have little to no anabolic effects BUT
- doesn’t effect MPS
- shown to effect CPS
- found in tendons
= strengthens connective tissues structure and tendons which means less injury
what strengthens connective tissues structure and tendons which means less injury
rhGH
CPS
collagen protein synthesis
anabolic-androgenic steroid
testosterone derivatives
how to get best results from testosterone
couple with exercise. Exercise and testosterone give additive effects
hypertrophy
muscle fibre growth
hyperplasia
more muscle fibres
most common form of muscle growth in humans
hypertrophy - increased muscle fibre area
effects of testosterone
- increased fibre area
- increased satellite cell number and myonuceli number in dose-response manner
what does testosterone act on
- androgen receptors
- myonuclei satellite cells
what gives testosterone a potential longer term advantage
the increase in myonuclei satellite cells remain for many at least 2 years, becuase they have a very slow turn over. This means that upon training, greater hypertrophy can still be obtained once administration has stopped
= muscle memory
performed in rats, not humans, Begs question of how long ban should be
can steroids be used to help increase muscle mass of the elderly?
steroids wil give a 3% increase in muscle muscle and final performance
- athletes are finally tuned machines, 3% is a big difference
- elderly are not working at optimum and so improvement would be negligible. They would benefit more from excercise
- there are also lots of side effects to steroid use
summary of IGF-1 use
- local action is important
- activates canonical pathway, but debatable as to whether it is essential for hypertrophy
- GH increases circulation IGF-1 but does not increases MPS
- GH does increase CPS
summary of testosterone use
- hypertrophic at pharmacological doses
- when knocked out it ameliorates normal hypertropgy
- carting levels within physiological range seem to have no effect
- not a linear dose-response relationship
male side effects of anabolic steroids
- baldness
- reduced sperm count
- breast development
- shrunken testicles
- increased risk of prostate cancer
- splayed teeth
- overgrown forehead
- severe acne
female side effects of anabolic steroids
- facial and body hair growth
- loss of breasts
- swelling of clitoris
- deepened voice
- increased sex drive
- problems with periods
- hair loss
- sever acnes
serious side effects of anabolic-androgenic steroids (AAS)
- heart attack or stroke
- kidney or liver tumour
- hypertension
- blood clots
- fluid retention
- high cholesterol
- prostate cancer
AAS
anabolic-androgenic steroids
gene doping
misuse of gene therapy
- the non-therapeutic use of genes, genetic elements and or cells that have the capacity to enhance athletic performance (WADA ‘01)
principle of gene therapy
- delivery to a cell of a therapeutic gene that may correct an abnormal gene
- directed primarily at a single gene disorder e.g muscular dystrophy, CF
- bodies improve NATURALLY post gene doping making it difficult to detect
why is gene doping hard to detect
because bodies improve/change naturally post GD
2 basic types of gene transfer
- germ line gene transfer / transgenesis
- somatic gene transfer
germ line gene transfer
- genetic material injected into nucleus of an early embryo before differentiation into somatic cells
- ensures that the GM is present in all cells and future generations
- not currently possible in humans = master breed
somatic gene transfer
- changing gene in an adult
- basis of gene therapy
what functions are targeted by gene therapy
- improving muscle mass strength
- improving oxygen delivery
- improving oxygen utilisation
genes that improve muscle mass strength
IGF1
Myostatin
genes that improves oxygen delivery
EPO
VEGF
genes that increase oxygen utilisation
PGC-1a
PPAR delta
PEPCK
gene therapy for enhanced muscle mass
transgene manipulator of IGF-1 expression causes over expression of IGF-1 in localised muscle = increased muscle mass
MICE
Findings of IGF-IEa gene transfer in rats
when combined with strength training, adaptations are enhanced
- increased muscle mass
- increased isometric force
problem of transferring rat studies of IGF-IEa to humans
would need exactly the same levels of gene expression in both biceps for symmetry. Otherwise performance would be affects by balance etc.
Difficult to scale up
what is the myostatin gene
GDF-8 is a negative regulator of muscle mass
GDF-8
myostatin gene. negative regulator of muscle mass
Belgian Blue Cattle
double muscle phenotype caused by lack of GDF-8 gene (myostatin)
shows association not prove causality
what happens to GDF-8 knockout mice
hypertrophy
no brakes on muscle growth, GDF8 is an inhibitor of MPS
effects of lacking in myostatin
results in excessive muscle growth BUT impaired force generation.
this is not a concern for body builders where aesthetics > performance
what is blood doping used for
to increase VO2max
- blood infused during VO2 max
- done wrong, can causes death
safer version of blood doping
EPO
what is EPO
erythropoietin - medical therapy for kidney failure
how does EPO work
- glycoprotein produced by kidney in response to low oxygen
- stimulates bone marrow to make more RBC
- # synthetic EPO has same effect
- increase in RBC for oxygen transport
- increase VO2max for endurance
BUT
risk of increased viscosity of the blood = heart attack and stroke
risk of EPO
increased viscosity of blood = hypotension = heart attack and stroke
microdoping
small changes which are safer and harder to detect
EPO mouse and monkey gene transfer studies
- adenovirus was used to deliver EPO gene to mouse and monkeys
- mouse hematocrits increase from 49-81%
- monkeys hematocrits increased from 40-70%
BUT blood thinning was required to keep animals alive becuase the EPO production had no switch off - body is an integrated system. If you change one thing, you will cause off targets effects of another which are usually dangerous
why does doping have so many side effects
body is an integrated system. Change one thing and you will often get off-target effects of another part of the system which usually cause adverse effects
VEGF
vascular endothelial growth factor
application of VEGF
- improves micro circulation
- extensively tested in clinical trials for ischaemic efficacy in cardiac & skeletal muscle disease
- limited success bc of complex regulation of angiogenesis
microcirucaltion
microcirculation is the circulation of the blood in the smallest blood vessels, the microvessels of the microvasculature present within organ tissues
ischaemic
inadequate blood supply to organ or part of body, particularly the heart muscle
genes that increase oxygen utilisation
PGC-1alpha
PPAR delta
PEPCK
PGC-1alpha
- coactivator regualtion gene involved in energy metabolism
- links external stimuli and regulation of mitochondrial biogenesis
- master regulator of mitochondrial biogenesis
PPAR delta
nuclear receptor proteins that function as transcription factors
PEPCK
phosphoenolypyruvate carboxykinase
- rate limiting enzyme of gluconeogenesis
rate limiting enzymes of gluconeogenesis
PEPCK
effect of over expression of PCG-1alpha in transgenic mice
- increased mitochondrial biogenesis bc master regulator
- muscle appear redder due to myoglobin
- cytochrome C is marker for increased mitochondrial content
- motor protons such as slow troponin and slow myosin are unregulated which is unexpected
unexpected results of over expression of PCG-1alpha in transgenic mice
Motor proteins such as slow troponin and slow myosin are unregulated
what is the marker for mitochondrial content
cytochrome C
effect of PPAR delta in mice
- darker muscle fibres
- more oxidative activity
- more mitochondria
- faster running time
Paper on over expression of PEPCK
was not a hypothesis driven paper. showed off-target effects of manipulation PEPCK mouse showed: - greater distance ran - RER below 1, so mostly burning fat - more mitochondria suggests that PEPCK gives endurance
does over expression of PEPCK give endurance? base on mouse paper findings
- PEPCK mouse showed changes for improved enduracne
BUT, was this the result of PEPCK or greater training?
the PEPCK ran further & longer, so unsure if the improvements are from the increased training or PEPCK.
Did PEPCK cause the change in behaviour so they exercised more?
Mouse to man for gene therapy
- most gene therapy shows impressive results in animal models of human disease
- but mice are small and tough creatures
- most used high vector doses, how will these affect man?
- -there was limited spread of any vector system used intramuscularly
- much have small muscles which I’ve impressive results, how will this scale up to human muscle which are very large in comparisons
risk of gene doing
uncontrolled expression!
- EPO causes increased heamtocrit leading to stroke and heart failure
- GH &IGF1 have risk of oncogenesis
- insertional mutagenesis
- myostatin reduces specific force
Case studies of naturally occurring genetic advantage
Finnish cross country skier accused of blood doping in 1964
- 15% more RBC than normal
- EPO receptor mutation in family which removed the switch off EPO function
Myostatin mutation in young boy
- born with v muscly phenotype
- similar to belgian blues cow
should they be able to compete?
what determines type of doping
physiological determinants of performance
what is the overall goal of AAS use
increase muscle size, for aesthetics or strength and power
what is the overall goal of EPO use
increase oxygen carrying capacity of blood and delivery, for improved endurance
why is it difficult to test drugs taken by athletes
they take them at doses that are not ethically compatible with mainstream scientific research. Dose-Response effectiveness if subject to speculation
Is gene doping a concern
been viewed as the new frontier of doping but no evidence of practising in sport, despite results in rodents.
There is a lot of problems with legitimacy and ethics of gene therapy
